Environmental exposure to foreign chemicals with estrogenic and other endocrine activities is widespread and is proposed to impact adversely on the health of humans, fish and wildlife. Exposure to xenoestrogens and other endocrine-disrupting chemicals has been associated with a variety of developmental and reproductive abnormalities, with observed toxicities ranging from infertility in rodents and domestic animals, to abnormal reproductive behavior and development in birds, to decreased hormone levels and early mortality in fish. This project investigates the actions of environmental chemicals that exert reproductive toxicities, with special emphasis on environmental estrogens and anti-androgens that induce gonadal toxicities in exposed mammals. A major goal of these studies is to elucidate the role of aryl hydrocarbon (Ah) receptor and its interactions with estrogen receptor and androgen receptor in mediating environmental chemical-induced testicular toxicities using cell-based and in vivo rodent models. A second major goal is to elucidate the action of environmental chemicals that exert endocrine disruptor activity indirectly, through the actions of protein kinases on nuclear receptor-dependent transcription, as exemplified by the action of methoxyacetic acid, the active metabolite of the industrial solvent ethylene glycol monomethyl ether. The specific aims of this project are: 1) to elucidate the role of Ah receptor in the estrogen receptor-stimulatory actions of xenoestrogens;2) to determine the contribution of Ah receptor to the male reproductive toxicities associated with anti-androgenic environmental chemicals;and 3) to investigate the effects of methoxyacetic acid on the transcriptional activity of androgen receptor and estrogen receptor and its impact on the contribution of these nuclear receptors to environmental chemical-induced testicular toxicities. These studies will enhance our understanding of the nuclear receptor-dependent mechanisms through which endocrine-active environmental chemicals induce male gonadal toxicities, and may, ultimately, help to identify strategies to improve the detection and prevention of adverse effects in exposed individuals.